Therapeutically harnessing anti-viral resident memory T cells in solid tumors

利用抗病毒驻留记忆 T 细胞治疗实体瘤

• 批准号: 10586695
• 负责人: Pamela Rosato
• 金额: $ 50.67万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586695
• 关键词: 2019-nCoV; Address; Automobile Driving; Blood Tests; CD8-Positive T-Lymphocytes; Cell physiology; Cells; Cellular immunotherapy; Clinic; Clinical; Complement; Cytomegalovirus; Data; Detection; Development; Environment; Epstein-Barr Virus Infections; Functional disorder; Human; Human Herpesvirus 4; Immune; Immunologic Surveillance; Immunologics; Immunotherapy; Infection; Inflammatory; Influenza A virus; Knowledge; Malignant Neoplasms; Memory; Messenger RNA; Methods; Modality; Modeling; Mus; Natural Immunity; Patients; Peptides; Population; Predisposition; Production; Resistance; Slice; Solid Neoplasm; Specificity; Stains; System; T-Lymphocyte; Testing; Therapeutic; Tissues; Translations; Treatment Efficacy; Tumor Antigens; Tumor Immunity; Vaccines; Viral; Viral Antigens; Virus; Virus Diseases; Work; adaptive immune response; adaptive immunity; anti-PD-L1; cancer immunotherapy; cell killing; clinical translation; clinically significant; combinatorial; cytokine; cytotoxic; exhaustion; human model; immune checkpoint blockade; in vivo; influenza infection; innovation; melanoma; mouse model; neoplasm immunotherapy; neoplastic cell; novel; novel strategies; pathogen; programmed cell death ligand 1; recruit; targeted treatment; tissue resident memory T cell; translational therapeutics; tumor; tumor growth

PROJECT SUMMARY/ABSTRACT Recent studies have revealed an abundance of resident memory T cells (TRM) specific for viral infections in a wide range of tumors, often outnumbering cancer-specific T cells. As these cells lack specificity to tumor antigens, they are spared from the hallmark exhaustion/dysfunction of tumor-specific T cells. To this end, we developed a novel immunotherapy which taps into immunostimulatory virus-specific TRM functions through treatment with viral peptides to break the immunosuppressive tumor environment. Reactivating virus-specific TRM with peptide was sufficient to restrict tumor growth in mice and when combined with checkpoint blockade, promoted durable tumor clearance. Mice that cleared tumors were protected from tumor re-challenge, suggesting anti-tumor immunity was established. Virus-specific TRM represent a major part of the tumor immune environment and can be leveraged therapeutically, yet there is a clinically significant gap in knowledge regarding the mechanisms of tumor clearance and how to optimally harness these cells. The objectives in this proposal are to determine (i) mechanism of tumor cell killing and durable tumor immunity, (ii) the impact of viral specificity on TRM function and therapeutic efficacy, and iii) define the optimal modality to reactivate virus-specific TRM. Using both mouse and human systems, this study addresses an innovative perspective connecting antiviral memory cells to tumor immunotherapy using cutting edge methods. We will complement mouse studies with combinatorial tetramer staining to enable simultaneous profiling of T cells specific for an expanded panel of viruses and vaccines in patient tumors. Completion of these aims will advance our understanding of tumor immunosurveillance and TRM function in mice and humans, and identify new target T cell populations for tumor immunotherapy. This contribution is expected to be significant because it will provide a strong scientific framework to expand the efficacy and utility of virus-specific TRM therapy, and enable the development of novel strategies leveraging these potent immune activating cells.

项目摘要/摘要 最近的研究表明，对A中的病毒感染具有丰富的居民记忆T细胞（TRM） 广泛的肿瘤范围，通常比癌症特异性T细胞超过肿瘤。由于这些细胞对肿瘤缺乏特异性 抗原，它们免于肿瘤特异性T细胞的标志性疲惫/功能障碍。为此，我们 开发了一种新型免疫疗法，该疗法通过 用病毒肽治疗以打破免疫抑制性肿瘤环境。重新激活病毒特异性 具有肽的TRM足以限制小鼠的肿瘤生长，并且与检查点阻断相结合时， 促进了耐用的肿瘤清除率。清除肿瘤的小鼠免受肿瘤的重新挑战，表明 建立了抗肿瘤免疫。病毒特异性TRM代表肿瘤免疫环境的主要部分 并且可以通过治疗杠杆杠杆来杠杆，但是关于 肿瘤清除的机制以及如何最佳利用这些细胞。该提议中的目标是 确定（i）肿瘤细胞杀死和耐用肿瘤免疫的机制，（ii）病毒特异性对 TRM功能和治疗功效，iii）定义了重新激活病毒特异性TRM的最佳方式。使用 鼠标和人类系统，本研究都涉及连接抗病毒记忆的创新视角 使用尖端方法对细胞进行肿瘤免疫疗法。我们将与小鼠研究相辅相成 组合四聚体染色以同时对特异性的T细胞进行分析 患者肿瘤中的病毒和疫苗。这些目标的完成将提高我们对肿瘤的理解 小鼠和人类的免疫监视和TRM功能，并鉴定肿瘤的新靶T细胞群体 免疫疗法。预计这一贡献将是重要的，因为它将提供强大的科学 扩大病毒特异性TRM疗法的功效和实用性的框架，并能够发展新颖 利用这些有效的免疫激活细胞的策略。